CN121287724A - A mesalazine colon-targeted drug delivery system, its preparation method, and its application. - Google Patents

Abstract

This invention discloses a mesalazine colon-targeted drug delivery system, its preparation method, and its application, belonging to the field of pharmaceutical formulation technology. The delivery system of this invention includes a mesalazine drug carrier backbone, an enzyme-sensitive component, and a pH-sensitive coating. The enzyme-sensitive component is coated on the outer layer of the mesalazine drug carrier backbone or mixed with it. The pH-sensitive coating is coated on the outer layer of the enzyme-sensitive component or on the outer layer of a mixture of the enzyme-sensitive component and the mesalazine drug carrier backbone. This invention employs a unique enzyme-sensitive + pH-sensitive double-layer coating technology, effectively protecting mesalazine from enzymatic degradation in the acidic environment of the stomach and the upper small intestine, significantly reducing premature drug release and systemic absorption; ensuring efficient and concentrated release of mesalazine in the colonic environment; improving the bioavailability of mesalazine in colonic lesions and enhancing local therapeutic effects; and reducing systemic exposure to mesalazine, thus reducing potential systemic adverse reactions.

Description

Mesala Qin Jiechang targeted drug delivery and transport system and preparation method and application thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a mesalamine Qin Jiechang targeted drug delivery and transport system, a preparation method and application.

Background

Inflammatory Bowel Disease (IBD), particularly ulcerative colitis, is a chronic recurrent disease whose lesions are mainly concentrated in the colonic area. Mesalazine (Mesalazine) is used as a first-line drug for treating IBD, and the core mechanism of action is to exert anti-inflammatory effects through local action. However, before the oral mesalazine preparation reaches the colon, part of the medicine is easily absorbed or degraded in the upper sections of the stomach and the small intestine, so that the concentration of the medicine finally reaching the lesion part is low, and the full efficacy is difficult to be exerted.

Currently available mesalamine Qin Jiechang targeting preparations are mostly dependent on techniques such as pH sensitive coating or slow-release matrix tablets to realize targeted release. The original research patent adopts a micropill coating (three-layer coating) technology, the method is complex in process flow, and can cause individual difference in drug release due to preparation difference or in-vivo environmental fluctuation, other prior art also has defects, such as complex process steps, wherein CN11258757A relates to the preparation of pH buffer particles and sustained-release tablets, CN105456223A realizes a sustained-release effect through the micropill technology, and has the defects of complex process and easiness in being influenced by individual difference, and CN105902500B discloses a mesalazine enteric-coated positioning controlled-release preparation which has complex technical scheme and combines multiple mechanisms such as ethylcellulose diffusion controlled release, pH sensitivity, bioadhesion and the like. While such a multi-layer composite system is intended to achieve colon localization, it is complex in process and has a low efficiency of the controlled release mechanism. The traditional dosage forms have the problems that the drug release is inaccurate, the bioavailability of the drug at the colon part is low, the untargeted released drug can cause gastrointestinal side effects and the like, and the clinical treatment requirements are difficult to meet.

Therefore, development of a mesalamine Qin Jiechang targeting preparation technology which is stronger in targeting, more accurate and stable in release, simpler and more convenient in preparation process and capable of effectively reducing individual difference is needed, so that the technical defects that the local drug concentration is insufficient and the slow release effect is not ideal due to early release of drugs in the stomach and small intestine in a traditional preparation, the accurate colon targeting cannot be realized, the preparation process is complex, the consistency among batches is poor are overcome, the efficient and concentrated release of the drugs at colon lesion sites is ensured, and the clinical curative effect and the medication safety of mesalamine in treating inflammatory bowel diseases are further improved.

Disclosure of Invention

Therefore, the invention aims to provide a mesalamine colon targeted drug delivery and transport system, which realizes local high-concentration release and explosive release of mesalamine in the colon, thereby achieving the purposes of effectively protecting the enzymatic degradation of mesalamine in gastric acid environment and upper sections of small intestine, obviously reducing the advanced release and systemic absorption of drugs, ensuring the efficient and concentrated release of mesalamine in the colon environment, simplifying the production process, improving the bioavailability of mesalamine in colon focus, enhancing the local treatment effect, reducing the systemic exposure of mesalamine and reducing the potential systemic adverse reaction.

Another object of the invention is to provide a method for preparing said transport system.

The invention also aims to provide an application of the transport system or the transport system prepared by the preparation method in preparation of drugs for targeted drug delivery of mesalamine Qin Jiechang.

Another object of the present invention is to provide a mesalazine colon targeted drug delivery capsule.

In order to achieve the above object, the present invention provides the following technical solutions:

The invention provides a mesalamine Qin Jiechang targeted drug delivery and transport system, which comprises a mesalamine drug carrier framework, an enzyme-sensitive component and a pH-sensitive coating, wherein the enzyme-sensitive component is coated on or mixed with the outer layer of the mesalamine drug carrier framework, and the pH-sensitive coating is coated on the outer layer of the enzyme-sensitive component or the outer layer of the mixture of the enzyme-sensitive component and the mesalamine drug carrier framework.

Preferably, the mesalazine medicine carrier framework comprises mesalazine and a framework material, wherein the framework material comprises any one or more of microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and polyethylene glycol.

Preferably, the enzyme-sensitive component comprises an enzyme-sensitive material, and the enzyme-sensitive material comprises any one or more of starch, pectin, dextran, inulin, guar gum, sodium alginate and xylan.

Preferably, the pH sensitive coating comprises a pH sensitive polymer, and the pH sensitive polymer comprises any one or more of acrylic resin, hydroxypropyl methylcellulose phthalate and cellulose acetate phthalate.

The invention also provides a preparation method of the transport system, which comprises the steps of mixing mesalazine and a framework material, adopting a tabletting method or a granulating method to obtain mesalazine drug carrier frameworks, adding water into enzyme-sensitive materials to dissolve the enzyme-sensitive materials to obtain enzyme-sensitive coating liquid, coating the mesalazine drug carrier frameworks to obtain enzyme-sensitive coating particles, adding organic solvent into pH-sensitive polymers to dissolve the pH-sensitive polymers to obtain pH-sensitive coating liquid, and coating the enzyme-sensitive coating particles to obtain the mesalazine Qin Jiechang targeted drug delivery transport system;

Or the preparation method comprises the steps of mixing mesalazine, a framework material and an enzyme sensitive material, obtaining a mixture of an enzyme sensitive component and mesalazine drug carrier framework by adopting a tabletting method or a granulating method, adding an organic solvent into a pH sensitive polymer to dissolve the mixture to obtain a pH sensitive coating liquid, and coating the mixture of the enzyme sensitive component and the mesalazine drug carrier framework to obtain the mesalazine Qin Jiechang targeted drug delivery and transport system.

Preferably, the weight gain of the coating of the enzyme-sensitive coating liquid after coating is 5% -9%.

Preferably, the weight gain of the coating after the coating is carried out by the pH sensitive coating liquid is 8% -12%.

The invention also provides an application of the transport system or the transport system prepared by the preparation method in preparation of the drug for targeted drug delivery of mesalamine Qin Jiechang.

Preferably, the dosage form of the medicament comprises a solid preparation, and the solid preparation comprises a tablet, a granule or a capsule.

The invention also provides a mesalamine Qin Jiechang targeted drug delivery capsule, and the transport system or the transport system prepared by the preparation method is filled into the capsule to obtain the capsule.

The invention has the beneficial effects that:

The invention provides a mesalamine Qin Jiechang targeted drug delivery and transport system, which adopts a unique double-layer coating technical concept of enzyme sensitivity and pH sensitivity, wherein the pH-sensitive coating provides protection on the upper sections of the stomach and the small intestine, enzyme sensitive materials play a role in the special microbial enzyme environment of the colon, so that the enzyme degradation of mesalamine in the gastric acid environment and the upper sections of the small intestine is effectively protected, the advanced release and systemic absorption of drugs are obviously reduced, the efficient and concentrated release of mesalamine in the colon environment is ensured, the bioavailability of mesalamine in colon focus is improved, the local treatment effect is enhanced, the systemic exposure of mesalamine is reduced, the potential systemic adverse reaction is reduced, and the drug release mode with more stability and reliability and smaller individual release difference is realized.

The invention provides a preparation method of a mesalamine Qin Jiechang targeted drug delivery and transport system, which does not take pellets as drug cores, but adopts drug granules or tablets prepared by traditional solid preparation technologies such as tabletting, granulating and the like as carriers, thereby simplifying the preparation process and avoiding strict requirements on equipment and technological parameters in the pellet coating process. The preparation method provided by the invention has the advantages of controllable process, accurate colon targeting of the prepared transport system, high bioavailability and good industrialization feasibility.

Detailed Description

The invention provides a mesalamine Qin Jiechang targeted drug delivery and transport system, which comprises a mesalamine drug carrier framework, an enzyme-sensitive component and a pH-sensitive coating, wherein the enzyme-sensitive component is coated on or mixed with the outer layer of the mesalamine drug carrier framework, and the pH-sensitive coating is coated on the outer layer of the enzyme-sensitive component or the outer layer of the mixture of the enzyme-sensitive component and the mesalamine drug carrier framework.

In the invention, the mesalazine drug carrier skeleton preferably comprises mesalazine and a skeleton material, the skeleton material preferably adopts a hydrophilic or lipophilic polymer as the skeleton material, and in some embodiments, the skeleton material preferably comprises any one or more of microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC-Na), polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG).

In some embodiments, the mesalazine drug carrier skeleton preferably further comprises an auxiliary material, and the auxiliary material preferably comprises any one or more of a filler, a diluent, a binder, a disintegrating agent and a lubricant. In some embodiments, the auxiliary material preferably comprises any one or more of lactose, microcrystalline cellulose, povidone K30, croscarmellose sodium, crospovidone, and magnesium stearate. The crosslinked sodium carboxymethyl cellulose is used as a super-disintegrant, can rapidly absorb water and expand after the coating is dissolved, promotes the rapid disintegration of the particles, and provides a physical basis for the degradation of enzyme-sensitive materials and the explosive release of medicines.

In the application, the enzyme-sensitive component preferably comprises an enzyme-sensitive material, and the enzyme-sensitive material preferably comprises any one or more of starch, pectin, glucan, inulin, guar gum, sodium alginate and xylan. The application selects glucan, pectin or starch and the like as enzyme sensitive materials, which are not easy to degrade in the upper section of the small intestine, but the unique chemical bond structure (such as alpha-1, 6-glycosidic bond of the glucan) can be specifically hydrolyzed by bacterial enzymes specific to colon. In addition, the application eliminates the alkalization treatment in the traditional enzyme-sensitive coating process, and the pH-sensitive outer layer provides protection through the unique coating sequence of 'enzyme-sensitive inner layer-pH-sensitive outer layer', thereby eliminating the necessity of alkalization treatment and simplifying the process.

In some embodiments, the enzyme-sensitive component preferably further comprises an auxiliary material, wherein the auxiliary material preferably comprises any one or more of a film forming agent, a slow release agent, a glidant, an anti-blocking agent and a plasticizer. In some embodiments, the auxiliary material preferably comprises any one or more of hydroxypropyl methylcellulose, talcum powder and polyethylene glycol.

In the present invention, the pH-sensitive coating preferably comprises a pH-sensitive polymer, the pH-sensitive polymer preferably comprises any one or more of acrylic resins, hydroxypropyl methylcellulose phthalate and cellulose acetate phthalate, and the acrylic resins preferably comprise an acrylic resin aqueous dispersion (Eudragit) L series or S series. In some embodiments, the series of acrylic aqueous dispersions L preferably includes Eudragit L100-55, and the series of acrylic aqueous dispersions S preferably includes Eudragit S100. The invention selects pH sensitive polymers such as Eudragit S100 or Eudragit L100-55, which are only dissolved at a specific pH, ensuring zero or very low release in the stomach and upper section of the small intestine.

In some embodiments, the pH sensitive coating preferably further comprises an auxiliary material, wherein the auxiliary material is preferably any one or more of a plasticizer, an anti-blocking agent, a glidant, an emulsifier and a lubricant. In some embodiments, the auxiliary material preferably comprises any one or more of diethyl phthalate, talcum powder, triethyl citrate, diethyl phthalate and polysorbate. The plasticizers such as diethyl phthalate, triethyl citrate and the like selected by the invention can increase the flexibility of the coating film and prevent the medicines from leaking in advance due to brittle fracture in the drying or gastrointestinal peristalsis process.

The invention adopts a double-gating mechanism of 'pH sensitive coating plus enzyme sensitive material', rather than single pH gradient or multi-layer pellet coating. The pH sensitive coating provides protection on the upper sections of the stomach and the small intestine, and the enzyme sensitive material plays a role in the special microbial enzyme environment of the colon, so that colon targeted release is realized more accurately, and a more stable and reliable drug release mode with smaller individual release difference is realized.

In the invention, the enzyme-sensitive component can be used as an independent layer to be coated on the mesalazine medicine carrier framework to form a layered structure, and can also be directly mixed with medicine to form a core framework to form an invagination structure. For the layered structure, the pH sensitive outer layer will completely expose the inner enzyme sensitive layer after dissolution in the small intestine. The colonic enzymes act on this exposed enzyme sensitive layer from the outside to the inside, relatively uniformly. When the enzyme sensitive layer is degraded to some extent, the drug core will begin to disintegrate and release. The advantage of this approach is that the "gating" effect of the release is stronger, the colonic targeting is higher and the leakage of drug in front of the colon can be reduced to a minimum. For the invaginated structure, after dissolution of the pH sensitive outer layer, the enzyme sensitive material and the drug in the drug matrix are exposed simultaneously. Colonic enzymes degrade enzyme sensitive materials from the various accessible surfaces of the scaffold. This degradation breaks the integrity of the matrix, allowing rapid release of the drug. The release rate in this manner is generally faster than in a layered structure, enabling a more thorough "burst" release. Meanwhile, the preparation process is relatively simpler because one additional coating step is omitted.

The invention also provides a preparation method of the transport system, which preferably comprises the steps of mixing mesalazine and a framework material, adopting a tabletting method or a granulating method to obtain mesalazine drug carrier frameworks, adding water into enzyme-sensitive materials to dissolve the enzyme-sensitive materials to obtain enzyme-sensitive coating liquid, coating the mesalazine drug carrier frameworks to obtain enzyme-sensitive coating particles, adding an organic solvent into a pH-sensitive polymer to dissolve the pH-sensitive polymers to obtain pH-sensitive coating liquid, and coating the enzyme-sensitive coating particles to obtain the mesalazine Qin Jiechang targeted drug delivery transport system;

Or the preparation method preferably comprises the steps of mixing mesalazine, a framework material and an enzyme sensitive material, obtaining a mixture of an enzyme sensitive component and mesalazine drug carrier framework by adopting a tabletting method or a granulating method, adding an organic solvent into a pH sensitive polymer to dissolve the mixture to obtain a pH sensitive coating liquid, and coating the mixture of the enzyme sensitive component and the mesalazine drug carrier framework to obtain the mesalazine Qin Jiechang targeted drug delivery and transport system.

In the present invention, when the mesalazine and the framework material are mixed, or when the mesalazine, the framework material and the enzyme sensitive material are mixed, the mixing mode is not particularly limited, and may be selected conventionally according to actual needs, and in some embodiments, a high-efficiency mixing granulator is used for mixing.

In the present invention, the tabletting method and the granulating method are not particularly limited, and may be routinely selected according to actual needs, and in some embodiments, granulation is performed by a spray granulating method.

In the present invention, the granulation is preferably followed by a drying process, in some embodiments preferably in a fluid bed dryer at 60 ℃ to a moisture content of <2%, in other embodiments preferably in an oven at 60 ℃ to a moisture content of <2%. The dried granules are preferably sieved for granule finishing, and the mesh number of the sieve is preferably 14-18 mesh, for example 14, 16 or 18 mesh.

In the invention, in the preparation process of the mesalazine drug carrier skeleton, auxiliary materials are preferably added, and the addition amount, the addition mode and the addition time of the auxiliary materials can be selected conventionally according to actual needs.

In the invention, the mass volume percentage of the enzyme-sensitive material in the enzyme-sensitive coating liquid is preferably 5% -15% (w/v, g/mL), for example 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15%. In the preparation process of the mesalazine medicine carrier framework, auxiliary materials are preferably added, and the addition amount, the addition mode and the addition time of the auxiliary materials can be selected conventionally according to actual needs.

In some embodiments of the present invention, it is preferred to spray coat the mesalazine drug carrier matrix with a fluid bed coater. The air inlet temperature of the spray coating is preferably 60-70 ℃, such as 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 or 70 ℃, and the spraying rate is preferably 5-12 mL/min, such as 5,6, 7, 7.5, 8, 9, 10, 11 or 12mL/min.

In the present invention, the weight gain of the coating after the coating by the enzyme-sensitive coating solution is preferably 5% -9%, for example 5%, 6%, 7%, 8% or 9%.

In the invention, the organic solvent preferably comprises an ethanol solution or an acetone-isopropanol mixed solution, wherein the volume ratio of ethanol to water in the ethanol solution is preferably (7-9.5): 1, such as 7:1, 7.5:1, 8:1, 8.5:1, 9:1 or 9.5:1, and the volume ratio of acetone to isopropanol in the acetone-isopropanol mixed solution is preferably 1 (0.5-1.5), such as 1:0.5, 1:1 or 1:1.5.

In the present invention, the mass volume percentage of the pH-sensitive polymer in the pH-sensitive coating solution is preferably 5% -15% (w/v, g/mL), for example, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15%.

In some embodiments of the present invention, it is preferred to spray coat enzyme-sensitive coated particles using a fluid bed coater. The air inlet temperature of the spray coating is preferably 40-55 ℃, such as 40, 42, 45, 48, 50, 52 or 55 ℃, and the spraying rate is preferably 6-15 mL/min, such as 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14 or 15mL/min.

In the present invention, the weight gain of the coating after the coating by the pH-sensitive coating solution is preferably 8% -12%, for example 8%, 9%, 10%, 11% or 12%.

Mesalazine has low solubility and strong pH dependence (acidic environment is hardly soluble, and the solubility in neutral to weakly alkaline environment is remarkably increased), and has the characteristic of exerting anti-inflammatory effect by local high concentration quick release of colon. The leakage problem of the medicine in the small intestine cannot be completely solved by simply relying on the pH sensitive coating, and the explosive release in the colon cannot be ensured. Meanwhile, even if the traditional slow release formulation can bring the medicine to the colon, the effective local concentration can not be achieved due to the too slow release, so that the curative effect is affected. The invention can realize the double control of 'pH gate control + enzyme triggering' by adding the enzyme sensitive material under the pH sensitive layer. The mechanism can ensure that the medicine is protected by the pH sensitive coating in the small intestine section, and after the medicine enters the colon, the pH sensitive layer is dissolved, and the internal enzyme sensitive layer is degraded by colonic enzymes, so that the quick and concentrated release of the medicine is realized, and the problem of insufficient targeting of a single-layer coating is solved. Meanwhile, the invention overcomes the defects that the traditional colon targeting preparation mostly adopts complex pellet coating technology, and further has long process flow and extremely severe requirements on equipment and operation parameters, adopts more general and simple pelleting or tabletting technology as a drug core carrier, avoids pellet cores, greatly simplifies the preparation technology, reduces the production technology threshold, obviously improves the consistency among batches and the product stability, and is easier to realize large-scale industrial production. In addition, conventional enzyme sensitive coatings often require an alkalizing treatment to promote precipitation and film formation of the enzyme sensitive material, maintain the solubility of the enzyme sensitive material, and prevent premature dissolution thereof in an acidic environment. The invention adopts a two-layer coating structure of 'enzyme sensitive inner layer- & gt pH sensitive outer layer', enzyme sensitive components are completely wrapped in the pH sensitive coating, the unique two-layer coating structure provides sufficient protection for the enzyme sensitive inner layer, the enzyme sensitive layer is not directly exposed to acidic or alkaline environment in the stomach environment after the whole coating preparation and drug oral administration, complex process steps are avoided, and more efficient and accurate colon targeted release is realized.

The invention also provides an application of the transport system or the transport system prepared by the preparation method in preparation of the drug for targeted drug delivery of mesalamine Qin Jiechang.

In the present invention, the dosage form of the drug preferably includes a solid preparation, and the solid preparation preferably includes a tablet, a granule or a capsule.

The invention also provides a mesalamine Qin Jiechang targeted drug delivery capsule, and the transport system or the transport system prepared by the preparation method is filled into the capsule to obtain the capsule.

In the invention, the capsules are preferably No. 0 hard capsules, and each capsule preferably contains 250-500 mg of mesalamine, such as 250, 300, 350, 400, 450 or 500mg.

The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.

In the following examples, conventional methods are used unless otherwise specified.

Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.

All of the experiments described below were performed in a laboratory environment compliant with GMP specifications and the instrumentation used was calibrated.

Example 1 Mesalazine pH/enzyme double sensitive sustained release capsule (layered structure)

1. Preparation of mesalazine drug carrier framework:

Raw materials comprise 250g of mesalazine, 150g of lactose, 80g of microcrystalline cellulose, 30 g of povidone K, and 5g of croscarmellose sodium;

Lactose and microcrystalline cellulose, among other things, act as fillers and diluents, providing proper volume and good compressibility, forming a homogeneous powder mixture. Microcrystalline cellulose serves as both a matrix material, a dry binder and a disintegrant, the fibrous structure of which is capable of providing physical structural support and facilitating the formation of particles and subsequent disintegration in the colon. Povidone K30 is used as a binder for wet granulation, forms a polymer chain in an ethanol solution, connects mesalazine and filler particles by intermolecular forces (such as hydrogen bonds) to form compact particles, improves the fluidity and compressibility of the particles, and ensures the uniformity of subsequent coating. The croscarmellose sodium is used as a super-disintegrant, and after the pH sensitive coating is dissolved, the cross-linked sodium carboxymethylcellulose is used as a super-disintegrant to promote the rapid disintegration of the drug core particles, accelerate the release of mesalazine and ensure the explosive release in the colon.

The preparation method comprises placing mesalazine, lactose, and microcrystalline cellulose in high-efficiency mixer granulator (such as GLATT GPCG 120,120), and mixing. Spray granulating with povidone K30 in ethanol (5% w/v, g/mL) as binder. The wet granules were dried in a fluid bed dryer (such as Glatt WSG 30) at 60 ℃ to a moisture content of <2%. The dried granules were sized by passing through a 16 mesh screen (standard screen, mesh size 1.18 mm). Adding croscarmellose sodium, and mixing in V-type mixer (such as Dukang Pharma V-Blender) for 10min to obtain mesalamine medicine carrier skeleton.

2. Coating of enzyme-sensitive components:

Raw materials of the medicine carrier skeleton of mesalazine are 495g, glucan is 30g, hydroxypropyl methylcellulose E5 g and talcum powder is 5g.

Wherein, the dextran is used as a main enzyme sensitive material, and the unique alpha-1, 6-glycosidic bond is not easy to hydrolyze in the upper segment of the small intestine of a human body, but is easy to degrade under the action of bacterial enzymes (such as glucanase) of the colon, thereby realizing a specific delay-trigger effect on mesalazine release. The hydroxypropyl methylcellulose E5 is used as a film forming agent and a sustained-release framework material, has good water solubility, can form a compact coating film together with glucan, provides the strength and toughness of the film, plays a certain control role in the degradation of glucan, delays the swelling and the too rapid disintegration of an enzyme sensitive layer in a non-colon environment, and ensures that the release of the drug in front of colon is very little. Talcum powder is used as glidant and anti-blocking agent to improve the spraying performance of coating liquid and the anti-blocking performance among particles.

The preparation method comprises dissolving dextran and hydroxypropyl methylcellulose E5 in appropriate amount of purified water (about 10% w/v), and stirring to dissolve completely. Adding talcum powder, stirring and dispersing uniformly to obtain the enzyme sensitive coating liquid. Spraying and coating the mesalazine medicine carrier skeleton by a fluidized bed coating machine (such as GLATT GPCG 120,120, provided with a bottom spray gun), wherein the air inlet temperature is 68 ℃, the spraying speed is 7.5mL/min, and the coating weight is controlled to be increased by about 5% -7% (monitored by a weighing method), so as to obtain the enzyme-sensitive coated granules.

3. Preparation of pH sensitive coating:

raw materials of the preparation comprise enzyme-sensitive coated particles 545g,Eudragit S100 60g, 6g of diethyl phthalate and 3g of talcum powder.

Among them, eudragit S100 is a main pH-sensitive polymer, which contains a large amount of carboxyl groups in its molecular structure, is highly non-ionized in gastric acid environment (pH < 7.0), and is hardly dissolved below pH 7.0, thereby perfectly protecting the inner layer structure and mesalazine from passing through the stomach and most of the small intestine. Only when the environmental pH rises above 7.0 (mimicking the small intestine end and colon environment) does the carboxyl groups begin to ionize, leading to dissolution of the polymer, exposing the enzyme sensitive inner layer. Diethyl phthalate is used as a plasticizer, and the intermolecular force among polymer chains is reduced, so that the flexibility of the coating film is increased, the coating is prevented from being brittle during gastrointestinal peristalsis and drying, and the integrity and stability of the coating layer are ensured. Talcum powder is used as an anti-adhesion agent, so that adhesion among particles is reduced in the coating process, and coating uniformity is ensured.

The preparation method comprises dissolving Eudragit S100 in appropriate amount of ethanol-water mixture (9:1 v/v) (about 15% w/v), and stirring to dissolve completely. Adding diethyl phthalate and talcum powder, and dispersing uniformly to obtain the pH sensitive coating liquid. The enzyme-sensitive coated granules are spray coated by a fluidized bed coating machine (such as GLATT GPCG 120,120), the air inlet temperature is 48 ℃, and the spraying rate is 10mL/min. The coating weight gain is controlled to be about 10% -12% (monitored by a weighing method), and the mesalamine Qin Jiechang targeted drug delivery and transport system is obtained.

4. Filling capsules, namely filling the coated mesalazine Qin Jiechang targeted drug delivery transport system into No. 0 hard capsules by adopting a semi-automatic or full-automatic capsule filling machine (such as Bosch GKF 700), wherein each capsule contains 250mg of mesalazine.

Example 2 mesalazine pH sensitive coated tablet capsule (containing enzyme sensitive matrix invagination structure)

1. Preparation of mesalazine skeleton tablet:

raw materials of the medicine comprise 500g of mesalazine, 100g of starch, 150g of microcrystalline cellulose, 30 g of povidone K and 5g of magnesium stearate.

Wherein starch is used herein as an enzyme-sensitive component which is degraded in the colon by bacterial enzymes such as amylase, thereby promoting disintegration of the tablet and release of mesalazine. Microcrystalline cellulose as a matrix material, filler, diluent and disintegrant provides bulk and hardness to the tablet and aids in the disintegration of starch in a particular environment, while having good compressibility. Povidone K30 is used as a binder to ensure cohesiveness of powder and formability of tablets and to improve hardness of tablets. Magnesium stearate is used as a lubricant, and a film is formed on the surface of the particles through adsorption, so that the friction force between the particles and a die is reduced, powder is prevented from adhering to a stamping die in the tabletting process, and the smooth surface of the tablet is ensured, and the tablet is easy to demould.

The preparation method comprises mixing mesalazine, starch, microcrystalline cellulose, granulating with water solution of povidone K30 (5% w/v), and drying the wet granule in oven at 60deg.C until water content is less than 2%. The dried granules were sized by passing through a 16 mesh screen (standard screen, mesh size 1.18 mm). Adding magnesium stearate, mixing, and pressing to obtain mesalazine skeleton tablet with weight of 775mg.

2. Preparation of a pH sensitive outer coating:

raw materials of the mesalazine skeleton tablet 775g,Eudragit L100-55 g, triethyl citrate 7g and talcum powder 3g.

Wherein Eudragit L100-55 acts as a pH sensitive polymer which begins to dissolve above pH 5.5, ensuring that the tablet is intact in the stomach and passes through the upper small intestine, progressively exposing the starch containing backbone. The triethyl citrate is used as a plasticizer to increase the toughness and elasticity of the coating film and prevent the coating from cracking during transportation and storage. Talcum powder is used as glidant and anti-sticking agent to avoid adhesion between tablets in the coating process.

The preparation method comprises dissolving Eudragit L100-55 in ethanol-water mixture (9:1 v/v) (about 10% w/v, g/mL), adding triethyl citrate and pulvis Talci, and dispersing. And (3) carrying out spray coating on the mesalazine skeleton tablet by adopting a high-efficiency coating machine to form a pH sensitive outer layer, wherein the air inlet temperature is 52 ℃, the spray rate is 12.5mL/min, and the coating weight gain is controlled to be about 8% -10% (monitored by a weighing method) so as to obtain the mesalazine Qin Jiechang targeted drug delivery transport system.

3. And (3) filling capsules, namely filling the coated mesalamine Qin Jiechang targeted drug delivery transport system into No. 0 hard capsules, wherein each capsule contains mesalamine 500mg.

Example 3 double-coated mesalazine capsules (outer pH sensitive, inner enzyme sensitive)

1. Preparation of mesalazine drug carrier framework:

raw materials of the medicine comprise 250g of mesalazine, 150g of lactose, 10g of crosslinked povidone and 10g of hydroxypropyl methylcellulose K4M.

Wherein lactose is used as filler. The cross-linked povidone is used as super-disintegrant, and has high cross-linked structure, so that the super-disintegrant has strong water absorption and expansion capacity, and can expand rapidly in water medium to promote rapid disintegration of particles, thereby accelerating drug release. The hydroxypropyl methylcellulose K4M is used as a hydrophilic framework material to provide certain viscosity and slow release effect, and is used as an auxiliary adhesive for dry granulation to increase the strength of the granules.

The preparation method comprises the steps of uniformly mixing mesalazine, lactose, crosslinked povidone and hydroxypropyl methylcellulose K4M, granulating by a dry method, and finishing to obtain the mesalazine drug carrier framework.

2. Coating of enzyme-sensitive components:

The raw materials comprise 420g of mesalazine medicine carrier skeleton, 40g of pectin, 10g of sodium alginate and 6000 g of polyethylene glycol.

Among them, pectin and sodium alginate are the main enzyme-sensitive materials, which are polysaccharides that are specifically degraded in the colon by pectase and alginic acid lyase produced by bacteria such as bacteroides. The synergistic effect of pectin and sodium alginate can provide more stable enzyme sensitivity and more controllable degradation speed, and ensure accurate release at colon part. Polyethylene glycol 6000 is used as a hydrophilic plasticizer and a cosolvent, so that the flexibility and the permeability of the coating film are improved, meanwhile, the dissolution and dispersion of pectin and sodium alginate in water are facilitated, and the uniformity of the coating liquid is improved.

The preparation method comprises dissolving pectin and sodium alginate in appropriate amount of water (about 10% w/v), and adding polyethylene glycol 6000. And (3) carrying out spray coating on the mesalazine medicine carrier framework by adopting a fluidized bed coating machine to form an enzyme-sensitive inner layer, wherein the air inlet temperature is 62 ℃, the spray rate is 10mL/min, and the coating weight gain is controlled to be about 7-9%, so as to obtain the enzyme-sensitive coated particles.

3. Preparation of pH sensitive coating:

Raw materials include 475g of enzyme-sensitive coating particles, 50g of Cellulose Acetate Phthalate (CAP), 5g of diethyl phthalate and 80 g of polysorbate 2.

Among them, cellulose Acetate Phthalate (CAP) is a pH-sensitive polymer that begins to dissolve above pH 6.0, ensuring that the formulation remains intact in the stomach and begins to dissolve in the middle section of the small intestine, exposing the inner layers. Diethyl phthalate is used as plasticizer to raise the mechanical strength and elasticity of the coating film and prevent cracking. Polysorbate 80 is used as an emulsifier and a wetting agent, which is helpful for dispersing and forming films of CAP in organic solvents, and improves the surface tension of coating liquid, so that the coating film is smoother and more uniform.

The preparation method comprises dissolving CAP in appropriate amount of acetone-isopropanol mixture (1:1 v/v) (about 10% w/v), and adding diethyl phthalate and polysorbate 80 to obtain pH sensitive coating solution. And (3) carrying out spray coating on the enzyme-sensitive coated particles by adopting a fluidized bed coating machine to form a pH-sensitive outer layer, wherein the air inlet temperature is 42 ℃, the spray rate is 7.5mL/min, and the coating weight is controlled to be increased by about 10% -12%, so that the mesalamine Qin Jiechang targeted drug delivery and transport system is obtained.

4. And (3) filling capsules, namely filling the coated mesalamine Qin Jiechang targeted drug delivery transport system into No. 0 hard capsules, wherein each capsule contains 250mg of mesalamine.

Comparative example 1 single pH sensitive coated mesalazine sustained release capsule (lacking enzyme sensitive layer)

The pH sensitive coating is directly carried out on the basis of the mesalazine drug carrier framework, and does not contain enzyme sensitive components.

1. A mesalazine drug carrier skeleton was prepared as in example 1.

2. Preparation of pH sensitive coating:

raw materials of the mesalazine granule comprise 495g,Eudragit S100 90g g of mesalazine core granule, 9g of diethyl phthalate and 5g of talcum powder.

The preparation method comprises dissolving Eudragit S100 in appropriate amount of ethanol-water mixture (9:1 v/v) (about 15% w/v), and stirring to dissolve completely. Adding diethyl phthalate and talcum powder, and dispersing uniformly to obtain the pH sensitive coating liquid. And (3) carrying out spray coating on the mesalazine drug carrier framework by adopting a fluidized bed coating machine, and controlling the coating weight gain to be about 18% -20% to obtain the mesalazine Qin Jiechang targeted drug delivery transport system.

3. And (3) filling capsules, namely filling the coated mesalamine Qin Jiechang targeted drug delivery transport system into No. 0 hard capsules, wherein each capsule contains 250mg of mesalamine.

Comparative example 2 mesalazine ordinary sustained release capsule (hydrophilic matrix tablet)

Reference example 2 shows a process for the preparation of mesalazine matrix tablet, but without any external coating, which is a conventional sustained release tablet.

1. Preparation of mesalazine skeleton tablet:

Raw materials of the medicine comprise 500g of mesalazine, 100M 200g of hydroxypropyl methylcellulose K, 70g of lactose and 5g of magnesium stearate.

The preparation method comprises mixing mesalazine, hydroxypropyl methylcellulose K100M and lactose uniformly, granulating by wet method, and drying the wet granule in oven at 60deg.C until the water content is less than 2%. The dried granules were sized by passing through a 16 mesh screen (standard screen, mesh size 1.18 mm). Adding magnesium stearate, mixing, and pressing to obtain mesalazine skeleton tablet.

2. And (3) filling capsules, namely filling the pressed mesalazine skeleton tablets into No. 00 hard capsules, wherein each capsule contains 500mg of mesalazine.

Comparative example 3 pH sensitive coated capsules (enzyme sensitive component in insufficient amount)

Reference is made to the preparation method of example 1, but the amount of glucan in the enzyme-sensitive material is significantly reduced.

1. A mesalazine drug carrier skeleton was prepared as in example 1.

2. Coating of enzyme-sensitive components:

raw materials include 495g of core particles, 5g of Dextran (Pharmacosmos, dextran T40), 15g of hydroxypropyl methylcellulose E5 (Dow Chemical, methocelTM E5 Premium LV), 5g of talcum powder (Luzenac, micronized Talc).

The preparation method is the same as in example 1, and the weight gain of the coating is controlled to be about 1% -2%.

3. The pH sensitive coating was prepared as in example 1, with the coating weight gain controlled between about 10% and 12%.

4. The filled capsules were as in example 1.

Comparative example 4 pH sensitive coated capsule (pH sensitive layer coating weight gain insufficient)

Reference is made to the preparation method of example 1, but the weight gain of the pH sensitive coating is significantly reduced.

1. A mesalazine drug carrier skeleton was prepared as in example 1.

2. Coating of enzyme-sensitive components the coating weight gain was controlled between about 5% and 7% as in example 1.

3. Preparation of pH sensitive coating:

raw materials enzyme-sensitive coated granules 545g,Eudragit S100 (Evonik Industries) 20g, diethyl phthalate (FISHER SCIENTIFIC) 2g, talc (Luzenac, micronized Talc 200,200) 1g.

The preparation method is the same as in example 1, and the weight gain of the coating is controlled to be about 3% -4%.

4. The filled capsules were as in example 1.

Comparative example 5 mesalazine pH/enzyme/pH triple sensitive sustained release formulation (pH sensitive inner layer, enzyme sensitive middle layer, pH sensitive outer layer)

1. A mesalazine drug carrier skeleton was prepared as in example 1.

2. First layer pH sensitive coating:

Raw materials of the medicine carrier skeleton 495g,Eudragit L100 28g of mesalazine, 2.8g of plasticizer (diethyl phthalate) and 1.4g of talcum powder. Wherein, the plasticizer is used for increasing the flexibility of the coating film to prevent the brittle fracture, and the talcum powder is used as an anti-sticking agent to prevent the particles from adhering in the coating process.

The preparation method comprises spray coating mesalazine medicine carrier skeleton with the prepared first layer of pH sensitive coating liquid in fluidized bed coating machine, air inlet temperature being 52 deg.C, spray rate being 12.5mL/min, and coating weight gain being controlled to about 6%.

3. Second enzyme sensitive coating (chitosan layer):

the raw materials comprise 524.7g of particles coated with a first layer, 30g of chitosan, 1.5g of glacial acetic acid, and a proper amount of ethanol and pure water as solvents. Wherein glacial acetic acid is used for dissolving chitosan to form coating liquid.

The preparation method comprises spray coating the granule coated with the first layer with the prepared second layer enzyme sensitive coating liquid in fluidized bed coater, air inlet temperature of 68deg.C, spray rate of 7.5mL/min, and coating weight gain of about 6%.

4. Third layer pH sensitive coating:

the raw materials are granules 556.2g,Eudragit L100 32g coated with a second layer, 3.2g of plasticizer (diethyl phthalate) and 1.6g of talcum powder, wherein the plasticizer and talcum powder are reused to ensure the integrity and smoothness of the final coating film.

The preparation method comprises spray coating the particles coated with the second layer with the prepared third layer pH sensitive coating liquid in a fluidized bed coating machine, wherein the air inlet temperature is 62 ℃, the spray rate is 10mL/min, and the coating weight gain is controlled to be about 6%. And the final coated granules were thoroughly dried.

5. Filling capsules were filled in the same manner as in example 1.

Test example 1 in vitro dissolution test

The capsules of examples 1, 2, comparative examples 1, 2,3 and 4 were subjected to dissolution measurement by using a paddle dissolution tester, referring to the dissolution measurement method of "chinese pharmacopoeia".

In order to simulate the pH environmental change of the medicine in human gastrointestinal tract, the experiment sets a three-stage continuous dissolution process, and the dissolution medium, the rotation speed and the duration time of each stage are as follows:

Stage 1 (simulated intragastric environment) using artificial gastric juice (pH 1.2) as dissolution medium at 120rpm for 2 hr.

Stage 2 (simulated intestinal environment) with artificial intestinal fluid (pH 6.8) as dissolution medium, rotation speed of 120rpm, and time of 3 hr.

Stage 3 (simulated colon environment) with artificial intestinal juice (pH 7.4, containing pig cecase) as dissolution medium at 120rpm for 7 hr.

The results are shown in Table 1.

Table 1 dissolution data (percent cumulative release):

As can be seen from the results in Table 1, when artificial gastric juice (pH 1.2) is taken as a dissolution medium (0-2 h), the pH sensitive coatings in the gastric juice are contained in the examples 1, 2 and the comparative examples 1 and 3, and the drug release amount in the gastric juice is extremely low (< 2%), so that the pH sensitive coatings effectively protect mesalamine from being damaged by gastric acid and are released in advance. Comparative example 4 shows that the release amount in gastric juice is significantly higher than that of example 1 due to insufficient weight gain of the pH sensitive coating, indicating that insufficient amount of the pH sensitive coating can lead to premature release of the drug in the stomach, significantly affecting its protective effect. Comparative example 2 is a normal sustained release capsule, which releases a large amount of drug in gastric juice, indicating that the normal sustained release dosage form cannot effectively protect the stability of drug in stomach, would cause a large amount of loss of drug before reaching the target site and increase systemic absorption.

When artificial intestinal juice (pH 6.8) is used as a dissolution medium (2-5 h), the drug release amount of the embodiment 1 is still low, which indicates that the pH sensitive coating begins to dissolve or swell in the upper section of the small intestine, but the enzyme sensitive inner layer can still effectively inhibit the rapid release of the drug, so that most of the drug can pass through the small intestine. The cumulative release amount of example 2 is slightly higher than that of example 1, and in the layered structure of example 1, the enzyme-sensitive inner layer serves as an independent physical barrier, and can effectively block drug release after the pH-sensitive outer layer is dissolved, and the drug needs to wait for hydration, swelling and even partial degradation of the enzyme-sensitive layer before starting release, so that the leakage amount in the small intestine is smaller. In the invaginated structure of example 2, the enzyme-sensitive material (starch) is in the backbone directly with mesalamine Qin Hunge. When the pH sensitive outer layer dissolves, the drug and enzyme sensitive material within the matrix are simultaneously exposed to the medium. Although starch itself is not easily degraded in the small intestine, the hydration and swelling process of the skeleton may cause a part of mesalazine to be released in advance, so that the leakage amount in the small intestine is slightly high. Comparative example 1 released significantly more drug than example 1, indicating that a single pH sensitive coating, while protecting in the stomach, may dissolve too rapidly in the small intestine, resulting in some drug being absorbed before reaching the colon. Comparative example 2 was released in the intestinal fluid continuously and slowly, more than 75% by 5 hours, which further confirmed its non-colonic targeting. Comparative example 3 the amount of enzyme-sensitive component released in the intestinal fluid was slightly higher than in example 1, probably due to the thinner enzyme-sensitive layer, which had reduced inhibitory effect on drug release. Comparative example 4 continued to release in large amounts in the intestinal fluid, exceeding 70% release by 5 hours, further verifying the deficiency of the pH sensitive coating.

With artificial intestinal juice (pH 7.4, containing pig cecase) as dissolution medium (5-10 h), the drug release amount of example 1 increased significantly in a short time, increased rapidly from 18.7% at 5.5h to 45.2% at 6.0 h, and reached a cumulative release rate of 90.5% at 8 h. This fully demonstrates that the pH-sensitive coating employed in the present invention cooperates with the enzyme-sensitive inner layer, and that the drug is released rapidly and intensively under the action of the colon-specific enzyme, achieving excellent colon targeting. Example 2 also showed significant burst release, with rapid increase in drug release over a short period of time, and eventually achieved a cumulative release effect of 97.2%. Example 1 released slightly faster after onset of colonic fluid than example 2, at the initial stage (within 0.5 hours) after entry into colonic fluid, example 1 released slightly faster than the invaginated structure example 2, as the enzyme sensitive layer achieved a more direct, more adequate exposure after dissolution of the pH sensitive coating. Nevertheless, in the long term (after 8 hours), the final cumulative release of both structures was similar, and excellent colon targeted release was achieved. Although an increase in drug release was also observed in the intestinal fluid for comparative example 1, the release rate and cumulative release amount were significantly lower than for example 1, to 10 hours, with a cumulative release amount of only 70.3%, indicating that the absence of the enzyme sensitive component, a single pH sensitive coating was difficult to provide sufficiently rapid and complete drug release in the colon. The drug of comparative example 2 was still released slowly in the colonic fluid, but in view of its large release in the stomach and small intestine, the meaning of colonic release was not great, and the release profile was gentle and no targeting was provided. The release amount of comparative example 3 in the intestinal juice is still significantly lower than that of example 1, and the insufficient amount of enzyme-sensitive material causes the degradation efficiency of enzyme to be reduced, and the ideal burst release effect cannot be achieved, which underscores the importance of the amount of enzyme-sensitive material in achieving accurate burst release. Comparative example 4 has a high release amount in colon fluid, but has little meaning of colon release due to its large release amount in stomach and small intestine, and has a gentle release curve and no targeting property.

Test example 2 in vitro dissolution test

The in vitro dissolution rates of example 1, comparative example 2 and comparative example 5 were measured by the same method as in test example 1, and the cumulative release percentage at each stage was measured, and the results are shown in table 2.

Table 2 dissolution data (percent cumulative release, average, n=18):

as can be seen from the results of table 2, all samples containing pH sensitive coatings showed very low drug release (< 2%) during the gastric juice (pH 1.2) phase, indicating that it effectively protected mesalazine, which verifies the key role of the pH sensitive material as "first pass gating".

The minimum drug release (14.3%) of example 1 at the intestinal fluid (pH 6.8) stage suggests that the structure of "pH sensitive outer layer + enzyme sensitive inner layer" can effectively utilize the gel barrier effect of the inner layer dextran to further delay drug leakage. In contrast, comparative example 5 had a higher release (35.1%) probably because of its three-layer structure at pH 6.8, after dissolution of the first coating, part of the drug leaked out through the chitosan layer of the middle layer.

In the colonic fluid (pH 7.4+enzyme) stage, the release speed and total amount of the embodiment 1 are highest, and the explosive release of mesalazine is realized, which proves that the two-layer coating structure of the invention can realize high-efficiency trigger release more accurately under the action of colonic enzyme. The release amount of comparative example 5 was significantly lower than that of example 1, indicating that the complex structure of its three-layer coating may prevent rapid degradation of the chitosan layer in the colon, resulting in incomplete release.

Test example 3 simulation of intestinal transit test (in vitro)

To further verify the colon targeting of the present invention, simulated intestinal transit experiments were performed using the capsules of example 1, comparative examples 1-4, respectively, by setting different transit time points, simulating the residence time of the drug in the stomach, small intestine and colon, and determining the drug release amount at each stage.

1. Devices that dynamically simulate the gastrointestinal system (e.g., TIM-1 or similar devices).

2. Simulation conditions:

(1) Stomach pH 1.2, stay 2 hours.

(2) Small intestine, pH 6.0-7.0, and stay for 3 hr.

(3) Colon pH 7.0-7.5, adding fresh feces homogenate (as colonic enzyme source), and standing for 6 hr.

3. The amount of accumulated released drug was measured by sampling at the end of each stage, and the results are shown in Table 3.

Table 3 simulated intestinal transit test data (cumulative percent released%):

It can be seen that the release amounts of example 1 and comparative examples 1 and 3 are very low in the stomach phase, again confirming the effective barrier effect of the pH sensitive coating against gastric acid, successfully avoiding non-targeted release of the drug in the stomach. Comparative example 4 resulted in significant release due to insufficient coating. Comparative example 2 showed significant drug release, demonstrating that it was not effective in protecting the drug in the stomach.

In the small intestine stage, the release amount of the example 1 in the small intestine stage is controlled to be the lowest, which shows that the enzyme sensitive inner layer has good inhibition effect on the early release of the medicine in the upper section of the small intestine. Comparative example 1 showed significantly higher release in the small intestine phase, further proving the problem that its single pH sensitive coating may release too quickly in the small intestine. Comparative example 3 the early release in the small intestine was slightly increased due to the insufficient amount of enzyme sensitive layer. Comparative example 4 and comparative example 2 released most of the drug at this stage.

In the colon phase, example 1 showed explosive release in the colon phase, with a cumulative release of up to 95.8%, indicating that the vast majority of the drug was released at the target site in the colon. Comparative example 1, while also releasing during the colonic phase, had significantly lower total release than example 1 and insufficient release, indicating that it was not as efficient as example 1 for colonic targeted release. Comparative example 3 also failed to reach the level of example 1 in the colon stage, again emphasizing the importance of enzyme sensitive material usage for burst release. Comparative example 4 and comparative example 2 have high release amounts in the colon phase, but their actual effective drug concentrations in the colon have been low in view of their early large release.

As can be clearly seen from the comparison of the test data of the comparative examples, the colon targeted drug delivery and transport system of the pH sensitive coating plus enzyme sensitive material provided by the invention has obvious superiority in the aspects of in vitro dissolution and simulated intestinal transport:

the effective protection of mesalazine on the upper sections of the stomach and the small intestine is realized, and the advanced release and absorption of the medicine are reduced to the maximum extent, so that the bioavailability of mesalazine is obviously improved;

Under the action of specific bacterial enzymes of the colon, the quick and concentrated release of mesalazine can be realized, the mesalazine is ensured to reach higher local medicine concentration at the focus part of the colon, and the treatment effect is enhanced;

Compared with a single pH sensitive coating or a common slow release dosage form, the design of the invention can more accurately deliver the drug to the colon, thereby improving the targeting and curative effects of the drug and reducing systemic adverse reactions.

These data strongly support the innovativeness, effectiveness and practicality of the present invention, further highlighting its advantages in the field of mesalamine Qin Jiechang targeted formulations. The invention has obvious differences with the prior art in the aspects of active ingredient (single medicine mesalazine), release mechanism (double accurate trigger of pH and enzyme), auxiliary material selection and action mechanism and preparation process.

The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (10)

1. The mesalamine Qin Jiechang targeted drug delivery transport system is characterized by comprising an mesalamine drug carrier framework, an enzyme-sensitive component and a pH-sensitive coating, wherein the enzyme-sensitive component is coated on or mixed with the mesalamine drug carrier framework, and the pH-sensitive coating is coated on the enzyme-sensitive component or the outer layer of the mixture of the enzyme-sensitive component and the mesalamine drug carrier framework.

2. The transport system of claim 1, wherein the mesalamine drug carrier scaffold comprises mesalamine and a scaffold material, and the scaffold material comprises any one or more of microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and polyethylene glycol.

3. The transport system of claim 1, wherein the enzyme-sensitive component comprises an enzyme-sensitive material, and wherein the enzyme-sensitive material comprises any one or more of starch, pectin, dextran, inulin, guar gum, sodium alginate, and xylan.

4. The transport system of claim 1, wherein the pH sensitive coating comprises a pH sensitive polymer, and wherein the pH sensitive polymer comprises any one or more of acrylics, hydroxypropyl methylcellulose phthalate, and cellulose acetate phthalate.

5. The method for preparing the transport system according to any one of claims 1-4, which is characterized by comprising the steps of mixing mesalazine and a framework material, obtaining mesalazine drug carrier framework by adopting a tabletting method or a granulating method, adding water into an enzyme-sensitive material to dissolve the enzyme-sensitive material to obtain enzyme-sensitive coating liquid, coating the mesalazine drug carrier framework to obtain enzyme-sensitive coated particles, adding an organic solvent into a pH-sensitive polymer to dissolve the pH-sensitive polymer to obtain pH-sensitive coating liquid, and coating the enzyme-sensitive coated particles to obtain the mesalazine Qin Jiechang targeted drug delivery transport system;

Or the preparation method comprises the steps of mixing mesalazine, a framework material and an enzyme sensitive material, obtaining a mixture of an enzyme sensitive component and mesalazine drug carrier framework by adopting a tabletting method or a granulating method, adding an organic solvent into a pH sensitive polymer to dissolve the mixture to obtain a pH sensitive coating liquid, and coating the mixture of the enzyme sensitive component and the mesalazine drug carrier framework to obtain the mesalazine Qin Jiechang targeted drug delivery and transport system.

6. The method according to claim 5, wherein the weight gain of the enzyme-sensitive coating solution after coating is 5% -9%.

7. The method according to claim 5, wherein the weight gain of the coating after the coating is performed by the pH sensitive coating liquid is 8% -12%.

8. Use of a delivery system according to any one of claims 1 to 4 or a delivery system according to any one of claims 5 to 7 for the preparation of a drug for targeted delivery of mesalamine Qin Jiechang.

9. The use of claim 8, wherein the dosage form of the medicament comprises a solid formulation, and wherein the solid formulation comprises a tablet, a granule, or a capsule.

10. A mesalamine Qin Jiechang targeted drug delivery capsule, characterized in that a delivery system according to any one of claims 1 to 4 or a delivery system prepared by the preparation method according to any one of claims 5 to 7 is filled into a capsule to obtain the capsule.